About this Research Topic
The mitochondrial proteolytic complex ClpXP, is composed of the serine protease ClpP and the ATP-dependent unfoldase ClpX. The primary function of ClpXP is to degrade selected substrates in the mitochondrial matrix thereby maintaining proteostasis in this organelle. Putative substrates targets of ClpP have been identified and include mitochondrial proteins involved in bioenergetic processes (e.g., tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS)), mitochondrial transcription and translation, protein import, and chaperones. The ClpXP complex has also been implicated in the regulation of heme biosynthesis, mitophagy, and mitochondrial dynamics. Both activators and inhibitors of ClpP have been shown to have profound effects on cell proliferation, highlighting the overall importance of this ATP-dependent protease.
The crystal structures of ClpP, ClpX, and ClpXP have been solved from several prokaryotes, while the X-ray structure of human ClpP has also been determined. A highly conserved protease, the ClpP protease consists of two heptameric rings that assemble into a tetradecameric proteolytic barrel. The ClpX ATPase forms a hexameric complex that binds on one or both ends of the ClpP barrel. The ClpX hexamer binds to hydrophobic pockets between the ClpP protomers to form the ClpXP complex. ClpX unfolds target proteins in an ATP-dependent manner and threads them into the ClpP barrel for degradation. ClpX facilitates the widening of the axial entrance pores of ClpP to promote entry of substrates into the ClpP proteolytic chamber.
Pharmacological activators of ClpP, such as the acyldepsipeptides (ADEPs) or the small molecule D9, also bind to the same hydrophobic pockets in ClpP (known as H sites), thus activating ClpP in the absence of ClpX by widening the entrance pore and facilitating entry of proteins into the proteolytic barrel. Research from multiple groups have discovered a novel class of ClpP activators. Based on the imipridone ONC201, this and other small molecules (the TR compounds), were shown to be potent regulators of ClpP activity and crystal structures confirmed the highly specific binding of these compounds to the H sites. Subsequent studies have identified other less potent molecules, also capable of activating ClpP.
Not surprisingly, there has been a recent explosion of interest in ClpP activators (ClpP agonists) as anti-cancer agents. ONC201 and ONC206 are ClpP agonists in >20 clinical trials for glioblastoma, ovarian, breast and other cancers and are well tolerated in patients. Particularly exciting have been some of the recent studies with diffuse intrinsic pontine glioma (DIPG), alone or in combination with other agents. Overexpression of ClpP has been observed in some cancer types, suggesting a cancer cell vulnerability. Treatment of cancer models with ClpP agonists, including the highly potent TR compounds, leads to selective matrix protein degradation, inactivation of OXPHOS, loss of mtDNA, an atypical stress response and cancer cell/tumor growth arrest. Importantly, these events are absent in ClpP null cells, demonstrating the exquisite specificity of these compounds. Despite this knowledge, the cellular anti-cancer mechanism of ClpP agonists remains to be fully elucidated.
Themes of Interest
1. Novel small molecule activators of ClpP; chemical scaffolds and analogs
2. Applications of ClpP activators as anti-cancer agents; rare or unusual cancers
3. Biological effects of ClpP activators on cell senescence or apoptosis; insight into mechanism of action
4. Mechanisms of resistance to ClpP activators; potential limitations to clinical applications
5. Contrasting effects of ClpP inhibitors
Because of the overwhelming amount of interest in ClpP agonists as pharmacological agents, we are soliciting Original Research or Mini Reviews on this topic.
The crystal structures of ClpP, ClpX, and ClpXP have been solved from several prokaryotes, while the X-ray structure of human ClpP has also been determined. A highly conserved protease, the ClpP protease consists of two heptameric rings that assemble into a tetradecameric proteolytic barrel. The ClpX ATPase forms a hexameric complex that binds on one or both ends of the ClpP barrel. The ClpX hexamer binds to hydrophobic pockets between the ClpP protomers to form the ClpXP complex. ClpX unfolds target proteins in an ATP-dependent manner and threads them into the ClpP barrel for degradation. ClpX facilitates the widening of the axial entrance pores of ClpP to promote entry of substrates into the ClpP proteolytic chamber.
Pharmacological activators of ClpP, such as the acyldepsipeptides (ADEPs) or the small molecule D9, also bind to the same hydrophobic pockets in ClpP (known as H sites), thus activating ClpP in the absence of ClpX by widening the entrance pore and facilitating entry of proteins into the proteolytic barrel. Research from multiple groups have discovered a novel class of ClpP activators. Based on the imipridone ONC201, this and other small molecules (the TR compounds), were shown to be potent regulators of ClpP activity and crystal structures confirmed the highly specific binding of these compounds to the H sites. Subsequent studies have identified other less potent molecules, also capable of activating ClpP.
Not surprisingly, there has been a recent explosion of interest in ClpP activators (ClpP agonists) as anti-cancer agents. ONC201 and ONC206 are ClpP agonists in >20 clinical trials for glioblastoma, ovarian, breast and other cancers and are well tolerated in patients. Particularly exciting have been some of the recent studies with diffuse intrinsic pontine glioma (DIPG), alone or in combination with other agents. Overexpression of ClpP has been observed in some cancer types, suggesting a cancer cell vulnerability. Treatment of cancer models with ClpP agonists, including the highly potent TR compounds, leads to selective matrix protein degradation, inactivation of OXPHOS, loss of mtDNA, an atypical stress response and cancer cell/tumor growth arrest. Importantly, these events are absent in ClpP null cells, demonstrating the exquisite specificity of these compounds. Despite this knowledge, the cellular anti-cancer mechanism of ClpP agonists remains to be fully elucidated.
Themes of Interest
1. Novel small molecule activators of ClpP; chemical scaffolds and analogs
2. Applications of ClpP activators as anti-cancer agents; rare or unusual cancers
3. Biological effects of ClpP activators on cell senescence or apoptosis; insight into mechanism of action
4. Mechanisms of resistance to ClpP activators; potential limitations to clinical applications
5. Contrasting effects of ClpP inhibitors
Because of the overwhelming amount of interest in ClpP agonists as pharmacological agents, we are soliciting Original Research or Mini Reviews on this topic.
Keywords: ClpXP Complex, Mitochondrial Proteostasis, ClpP Activators, Anti-Cancer Agents, Mitochondrial Function, ClpX ATPase, ClpP Agonists, ClpP Inhibitors
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